Currently there is no neuroprotective or neurorestorative therapy for Parkinson's disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous ...production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP(+)-lesioned or adeno-associated virus α-synuclein rat models of Parkinson's disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson's disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson's disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson's disease.
Time-of-flight MR angiography, though widely used after coil embolization, is associated with limitations owing to magnetic susceptibility and radiofrequency shielding following stent-assisted coil ...embolization. We evaluated the pointwise encoding time reduction with radial acquisition (PETRA) sequence in subtraction-based MRA (qMRA) using an ultrashort TE relative to TOF-MRA during the follow-up of stent-assisted coil embolization for anterior circulation aneurysms.
Twenty-five patients (3 men and 22 women; mean age, 59.1 ± 14.0 years) underwent stent-assisted coil embolization for anterior circulation aneurysms and were retrospectively evaluated using TOF-MRA and PETRA qMRA data from the same follow-up session. Two neuroradiologists independently reviewed both MRA findings and subjectively graded flow within the stents (relative to the latest DSA findings) and occlusion status (complete occlusion or neck/aneurysm remnant). Interobserver and intermodality agreement for TOF-MRA and PETRA qMRA were evaluated.
The mean score for flow visualization within the stents was significantly higher in PETRA qMRA than in TOF-MRA (
< .001 for both observers), and good interobserver agreement was reported (κ = 0.63). The aneurysm occlusion status of PETRA qMRA (observer 1, 92.0%; observer 2, 88.0%) was more consistent with DSA than with TOF-MRA (observer 1, 76.0%; observer 2, 80.0%), and there was a better intermodality agreement between DSA and PETRA qMRA than between DSA and TOF-MRA.
These findings indicate that PETRA qMRA is a useful follow-up technique for patients who have undergone stent-assisted coil embolization for anterior circulation aneurysms.
Aim
To investigate the molecular mechanisms of nitric oxide (NO)‐induced cytotoxic effect in human gingival fibroblast (HGF) cells.
Methodology
After sodium nitroprusside (SNP), as NO donor, was ...treated to HGF, viability was measured by MTT assay and apoptosis was determined by TUNEL and DNA fragmentation assay. Mitochondrial membrane potential was detected using confocal microscopy, and caspase activity assay was measured by spectrophotometer. Mitogen‐activated protein kinases (MAPK) activation, Bax/Bcl‐2 ratio and cytochrome c release were analysed by Western blot analyses. Cells were exposed to MAPK inhibitors (U0126, SB203580 and SP600125) before SNP treatment to investigate the effects of MAPK kinases on the NO‐induced apoptosis in HGF. Statistical analysis was performed using one‐way analysis of variance with the Student–Newman–Keuls post hoc test for multiple group comparison.
Results
Apoptosis was significantly increased (P = 0.011 and 0.0004, respectively) in the presence of SNP (1 and 3 mmol L−1) after 12 h in HGF. However, 1H‐1,2,4 oxadiatolo 4, 3‐a cluinoxaline‐1‐one (ODQ), a soluble guanylate cyclase inhibitor, did not block the decrement of cell viability by NO. SNP treatment induced the loss of mitochondrial membrane potential, release of cytochrome c, increased Bax/Bcl‐2 ratio and activation of caspases in HGF. Also, SNP treatment increased phosphorylation of MAPKinases and c‐Jun N‐terminal kinase (JNK) inhibitor (5 and 10 μmol L−1) rescued cell viability decreased by SNP in HGF (P = 0.024 and 0.0149, respectively).
Conclusion
Nitric oxide induced apoptosis in human gingival fibroblast through the mitochondria‐mediated pathway by regulation of Bcl‐2 family and JNK activation.
The cannabinoid (CB2) receptor type 2 has been proposed to prevent the degeneration of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. However, the mechanisms ...underlying CB2 receptor-mediated neuroprotection in MPTP mice have not been elucidated. The mechanisms underlying CB2 receptor-mediated neuroprotection of dopamine neurons in the substantia nigra (SN) were evaluated in the MPTP mouse model of Parkinson's disease (PD) by immunohistochemical staining (tyrosine hydroxylase, macrophage Ag complex-1, glial fibrillary acidic protein, myeloperoxidase (MPO), and CD3 and CD68), real-time PCR and a fluorescein isothiocyanate-labeled albumin assay. Treatment with the selective CB2 receptor agonist JWH-133 (10 μg kg(-1), intraperitoneal (i.p.)) prevented MPTP-induced degeneration of dopamine neurons in the SN and of their fibers in the striatum. This JWH-133-mediated neuroprotection was associated with the suppression of blood-brain barrier (BBB) damage, astroglial MPO expression, infiltration of peripheral immune cells and production of inducible nitric oxide synthase, proinflammatory cytokines and chemokines by activated microglia. The effects of JWH-133 were mimicked by the non-selective cannabinoid receptor WIN55,212 (10 μg kg(-1), i.p.). The observed neuroprotection and inhibition of glial-mediated neurotoxic events were reversed upon treatment with the selective CB2 receptor antagonist AM630, confirming the involvement of the CB2 receptor. Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.
Calpains are a family of calcium-dependent cysteine proteases that are ubiquitously expressed in mammals and play critical roles in neuronal death by catalyzing substrate proteolysis. Here, we ...developed two-dimensional gel electrophoresis-based protease proteomics to identify putative calpain substrates. To accomplish this, cellular lysates from neuronal cells were first separated by pI, and the immobilized sample on a gel strip was incubated with a recombinant calpain and separated by molecular weight. Among 25 altered protein spots that were differentially expressed by at least 2-fold, we confirmed that arsenical pump-driving ATPase, optineurin, and peripherin were cleaved by calpain using in vitro and in vivo cleavage assays. Furthermore, we found that all of these substrates were cleaved in MN9D cells treated with either ionomycin or 1-methyl-4-phenylpyridinium, both of which cause a calcium-mediated calpain activation. Their cleavage was blocked by calcium chelator or calpain inhibitors. In addition, calpain-mediated cleavage of these substrates and its inhibition by calpeptin were confirmed in a middle cerebral artery occlusion model of cerebral ischemia, as well as a stereotaxic brain injection model of Parkinson disease. Transient overexpression of each protein was shown to attenuate 1-methyl-4-phenylpyridinium-induced cell death, indicating that these substrates may confer protection of varying magnitudes against dopaminergic injury. Taken together, the data indicate that our protease proteomic method has the potential to be applicable for identifying proteolytic substrates affected by diverse proteases. Moreover, the results described here will help us decipher the molecular mechanisms underlying the progression of neurodegenerative disorders where protease activation is critically involved.
Background: It is important to assess contribution of calpain activation and identify substrates affected during neurodegeneration.
Results: Gel-based protease proteomics identified novel substrates that were cleaved in neurotoxin-treated culture and rat brain disease models.
Conclusion: These novel calpain substrates may confer protection against neurodegeneration.
Significance: Our findings contribute to better deciphering the molecular mechanism underlying the progression of protease-mediated neurodegeneration.
The effects of capsaicin (CAP), a transient receptor potential vanilloid subtype 1 (TRPV1) agonist, were determined on nigrostriatal dopamine (DA) neurons in the ...1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). The results showed that TRPV1 activation by CAP rescued nigrostriatal DA neurons, enhanced striatal DA functions and improved behavioral recovery in MPTP-treated mice. CAP neuroprotection was associated with reduced expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and reactive oxygen species/reactive nitrogen species from activated microglia-derived NADPH oxidase, inducible nitric oxide synthase or reactive astrocyte-derived myeloidperoxidase. These beneficial effects of CAP were reversed by treatment with the TRPV1 antagonists capsazepine and iodo-resiniferatoxin, indicating TRPV1 involvement. This study demonstrates that TRPV1 activation by CAP protects nigrostriatal DA neurons via inhibition of glial activation-mediated oxidative stress and neuroinflammation in the MPTP mouse model of PD. These results suggest that CAP and its analogs may be beneficial therapeutic agents for the treatment of PD and other neurodegenerative disorders that are associated with neuroinflammation and glial activation-derived oxidative damage.
Surgical revision of recurrent cerebral aneurysms is technically difficult. Therefore, coil embolization has been used as an alternative in these cases. The aim of this study was to evaluate the ...clinical and angiographic outcomes of coil embolization in patients with recurrent cerebral aneurysms after microsurgical clipping.
Between May 1999 and February 2016, nineteen patients with 19 recurrent aneurysms who previously underwent surgical clipping were treated by coil embolization.
Nine patients presented with subarachnoid hemorrhage (47.4%). The interval between surgical clipping and coil embolization was 143.5 ± 66.1 months (range, 43-276 months). Single- or double-catheter coil embolization was performed in 16 patients. A balloon (
= 1) and stents (
= 2) were used to assist the coil embolization in 3 patients. Immediate radiologic findings after coil embolization showed complete occlusion in 10 patients, a residual neck in 8 patients, and a residual sac in 1 patient. Procedure-related permanent morbidity occurred in 1 patient. The mean clinical follow-up was 58.3 ± 38.8 months. Poor clinical outcomes (modified Rankin Scale score = ≥3) at the end of the clinical follow-up were reported in 5 patients (26.3%). Angiographic follow-up was available for 12 patients (63.2%). Major recurrence was detected in 5 patients (41.7%), and a tendency for aneurysm regrowth rather than coil compaction was noted in all cases.
In our series, coil embolization for recurrent aneurysms after surgical clipping was feasible but had a high recurrence rate and tended to result in aneurysm regrowth rather than coil compaction.
The conical band structure is the cornerstone of graphene's ultra-broadband optical conductivity. For practical use of graphene in nonlinear photonics, however, substantial increases of the ...light-matter interaction strength will be required while preserving the promising features of monolayers, as the interaction of light with a single atomic layer is limited due to the extremely short interaction length and low density of state, particularly for the long-wavelength region. Here, we report that this demand can be fulfilled by random stacking of high-quality large-area monolayer graphene up to a requested number of layers, which leads to the electronic interaction between layers being effectively switched off due to turbostratic disorder. The nonlinear characteristics of randomly stacked multilayer graphene (RSMG), which originates from a thermo-modulational feedback mechanism through ultrafast free-carrier heating and temperature-dependent carrier-phonon collisions, show clear improvements in the terahertz (THz) regime with increasing layer numbers, whereas as-grown multilayer graphene (AGMG) exhibits limited behaviors due to strong interlayer coupling. This controllable nonlinearity enhancement provides an ideal prerequisite for developing efficient graphene-based THz photonic devices.
We investigate the thermal characteristics of a polymer-clad fiber laser under natural convection when it is strongly pumped up to the damage point of the fiber. For this, we utilize a temperature ...sensing technique based on a fiber Bragg grating sensor array. We have measured the longitudinal temperature distribution of a 2.4-m length ytterbium-sensitized erbium-doped fiber laser that was end-pumped at approximately 975 nm. The measured temperature distribution decreases exponentially, approximately, decaying away from the pump-launch end. We attribute this to the heat dissipation of absorbed pump power. The maximum temperature difference between the fiber ends was approximately 190 K at the maximum pump power of 60.8 W. From this, we estimate that the core temperature reached approximately 236 degrees C.
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